Configurationally Stable (S)- and (R)-α-Methylproline-Derived Ligands for the Direct Chemical Resolution of Free Unprotected β3-Amino Acids

Article abstract of DOI:10.1002/ejoc.201800120

Reported herein is a chemical method for the direct resolution of unprotected racemic β-substituted-β-amino acids (β³-AAs) that uses specially designed, stable, and recyclable α-methylproline-derived chiral ligands. The versatility of this methodology is unmatched by biocatalytic approaches. The method shows a broad synthetic generality for various aryl- or alkyl-substituted β³-AAs, and the new nonracemizable ligands can be accessed readily. Furthermore, the presented method produces an excellent stereochemical outcome and has a fully recyclable source of chirality, and the reaction conditions are operationally simple and convenient. The procedure has also been successfully applied to the scalable synthesis of the anti-HIV drug maraviroc.

Full text of DOI:10.1002/ejoc.201800120

DOI: 10.1002/ejoc.201800120
Full Paper
Chemical Resolution | Very Important Paper |
Configurationally Stable (S)- and (R)-α-Methylproline-Derived
Ligands for the Direct Chemical Resolution of Free Unprotected
3
ꢀ
-Amino Acids
Shengbin Zhou,[a,b][‡] Shuni Wang,
[a,b][‡]
Jiang Wang,
[a,b]
Yong Nian,[a,b] Panfeng Peng,[a,b]
Vadim A. Soloshonok,*[ and Hong Liu*
c,d]
[a,b]
Abstract: Reported herein is a chemical method for the direct can be accessed readily. Furthermore, the presented method
resolution of unprotected racemic ꢀ-substituted-ꢀ-amino acids produces an excellent stereochemical outcome and has a fully
3
(
ꢀ -AAs) that uses specially designed, stable, and recyclable α- recyclable source of chirality, and the reaction conditions are
methylproline-derived chiral ligands. The versatility of this operationally simple and convenient. The procedure has also
methodology is unmatched by biocatalytic approaches. The been successfully applied to the scalable synthesis of the anti-
method shows a broad synthetic generality for various aryl- or HIV drug maraviroc.
3
alkyl-substituted ꢀ -AAs, and the new nonracemizable ligands
II
Introduction
Tailor-made amino acids (AAs) are in extremely high demand
resolution of unprotected AAs through the application of Ni
complexes.
[
12]
[
1]
As detailed in Scheme 1, free racemic α-AAs 2
react readily under rather mild conditions with the tridentate
ligand (R)- or (S)-1 to form the tetracoordinate Ni complex
This transformation is a multistep process that re-
sults in the in situ formation of the ester/Schiff base to protect
the free α-AA-2. The absolute configuration of the α-AA resi-
due in (R,2R)-3 is thermodynamically controlled, and the ratio
[
2]
in nearly every sector of the healthcare industry. In particular,
II
3
[3]
unnatural ꢀ -AAs and their analogs are becoming an increas-
[
13]
(R,2R)-3.
ingly common structural feature in newly developed pharma-
[
4]
ceuticals. In this regard, the availability of structurally varied
[
12]
3
ꢀ
-AAs has become a critically important rate-determining fac-
[
14]
tor in the exploration of the rich biochemistry and applications
3
[5]
usually exceeds 98:2. The disassembly of purified complexes
of ꢀ -AAs. For practicality, biocatalyst-based approaches are
[
12]
(R,2R)-3 is performed under acidic conditions
to afford the
usually more commercially viable than purely chemical meth-
ods.[3,6]
3
target α-AAs (R)-2, along with a nearly quantitative recovery of
the stereochemically intact ligand 1. This process represents a
true chemical resolution that allows the transformation of all of
the starting racemate into the target enantiomer. In sharp con-
Furthermore, the resolution of racemic ꢀ -AAs might be
the most economically feasible approach, as we can readily ob-
tain the corresponding racemates through the Rodionov reac-
[
7]
[8]
tion. However, previously developed chemical or chemo-
3
enzymatic[9] methods do not work for free ꢀ3-AAs that require
trast, the reactions of racemic ꢀ -AAs 4 with ligand (R)-1 require
relatively harsh conditions, most likely because of the unfavor-
chemical protection steps.
3
II
able seven-membered chelated ring of the ꢀ -AA in the Ni
Owing to our interest in the synthetic methodology
for α-[
10]
[11]
complex (R,2S)-5. Nevertheless, if strong bases such as NaH,
KOtBu, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are used, li-
and ꢀ-AAs,
we initiated a research project on the
3
[
a] University of Chinese Academy of Sciences,
gand 1 reacts preferentially with one of the enantiomers of ꢀ -
No.19A Yuquan Road, Beijing 100049, China
E-mail: hliu@simm.ac.cn
http://sourcedb.cas.cn/sourcedb_simm_cas/yw/zjrcyw/201111/t20111121_
AAs 4 to enable the resolution process. For example, (R)-1 reacts
relatively enantioselectively with (S)-4 (R = aryl) to afford com-
plexes (R,2S)-5 in yields of up to 95 % and diastereomeric ratios
3
399263.html
[
13a]
of more than 90:10.
Through further work on these reac-
[
[
b] CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences,
tions, we found that the stereochemical integrity of ligands 1
has an innate limit. Thus, when the reactions were conducted
under slightly more forceful conditions, for example, at in-
creased temperatures or for longer reaction times, we detected
a noticeable degree of racemization at the proline stereogenic
center. For instance, in these cases, the routine control of the
enantiomeric purity of the recovered ligand 1 showed between
5
55 Zuchongzhi Road, Shanghai 201203, China
c] Department of Organic Chemistry I, Faculty of Chemistry, University of the
Basque Country UPV/EHU,
Paseo Manuel Lardiz a´ bal 3, 20018 San Sebastián, Spain
E-mail: vadym.soloshonok@ehu.eus
http://www.ikerbasque.net/vadym.soloshonok
[
[
d] IKERBASQUE - Basque Foundation for Science,
Maria Diaz de Haro 3, 48013 Bilbao, Spain
‡] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800120.
2
–13 % racemization (Supporting Information, Table S1, Fig-
ures S1–S6). Hence, it became clear that the structure of ligand
1 is rather incompatible with the harsh conditions required for
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3
Scheme 1. Application of proline-derived ligands (R)- or (S)-1 for the chemical resolution of free, unprotected α-AAs and the kinetic resolution of ꢀ -AAs.
the reactions with ꢀ-AAs. In this work, we present a solution to Scheme 2, we implemented a procedure based on N-Boc-α-
this problem through the design of a new family of ligands methylproline (10, Boc = tert-butyloxycarbonyl), which is com-
based on the nonracemizable α-methylproline. We disclose a mercially available in both the (S) and the (R) enantiomeric
new synthetic approach that allows structural diversity in the forms. As the amino group in 10 is Boc-protected, we formed
designed ligands, the evaluation of their stereochemical per- the amide bond by the mixed-anhydrate method. Although the
formances, and their application for the chemical resolution of consumption of both starting materials 8 and 10 was almost
ꢀ-substituted-ꢀ-amino acids. We also demonstrate the practical complete, the target product 11 was isolated in a somewhat
use of the developed procedure for the preparation of maravi- low yield of 62 %, most probably because of the vulnerability
[
15]
roc, an antiretroviral drug for the treatment of HIV.
of the Boc protecting group to the slightly acidic reaction me-
dium. However, we found this reaction quite reliable, reproduci-
ble, and operationally convenient for scaling up and, therefore,
satisfactory. On the other hand, the advantage of Boc-protec-
tion is that the deprotection of 11 is almost quantitative and
affords 12 in an average 98 % yield without the need for addi-
tional purification. The final stage of this process is a reductive
amination, which is a convenient and well-researched reaction
that shows tolerance to the steric bulk of the α-methylproline
moiety. It was rather stimulating to realize that the necessity to
develop a new procedure can result in an exciting synthetic
bonus. Thus, the reductive amination reaction with 12 and alde-
hydes 13 showed some exceptional generality and allowed the
preparation of various N-substituted derivatives under the
same standard reaction conditions. Taking advantage of this
methodological opportunity, we synthesized a series of new
ligands 14–17 bearing alkyl and benzyl substituents.
Results and Discussion
The established synthetic procedure for the large-scale prepara-
tion of proline ligands (S)- and (R)-1 includes the N-benzylation
of free proline, followed by a reaction with an o-aminobenzo-
[
16]
phenone derivative.
Quite surprisingly, attempts to repro-
duce this process with α-methylproline (6, Scheme 2) failed.
Thus, the reaction of 7 with benzyl or 3,4-dichlorobenzyl brom-
ide did not produce the expected N-benzylated product 9. This
problem was largely unanticipated but can be reasonably ra-
tionalized by the presence of the quaternary, tert-butyl-like sub-
stituent, which renders the corresponding S 2 substitution vir-
N
[
17]
tually impossible.
Thus, facing the need for the development of an entirely
new synthetic approach to α-methylproline-derived ligands, we
explored a series of options and focused on the cost, structure,
As we had reliable access to the α-methylproline-derived li-
and potential process scalability. Ultimately, as shown in gands 14–17, we decided to briefly explore their reactivity and
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Scheme 2. Synthetic approach to the family of α-methylproline-derived ligands (S)- and (R)-14–17.
stereocontrolling properties, as the known data relevant to the
reactions with ꢀ -AAs are limited solely to the reactions of N-
Table 1. Chemical resolution of ꢀ-phenyl-ꢀ-alanine 4a with new chiral ligands
14–17.
3
3
,4-dichlorobenzyl ligands such as 1. To this end, we conducted
3
a series of reactions between racemic ꢀ -AA 4a and ligands 14–
1
7, and selected data are collected in Table 1.
It follows from the data presented in Table 1, Entries 1–4 that
the nature of the substituent on the proline nitrogen atom does
not have a substantial effect on the stereochemical outcome of
the reaction. Thus, the chemical yields of the isolated nickel
complexes were in the range 54 (Table 1, Entry 2) to 83 %
(
Table 1, Entry 4), and the diastereomeric ratios were even
closer and varied between 95:5 (Table 1, Entry 1) and 88:12
Table 1, Entry 3). The observed subtle differences can be attrib-
(
II
Yield [%][b]
dr[c]
Entry
1[
Ligand
Ni complex
uted to the steric effects of the substituent on the stabilities of
the major and minor products under strongly basic conditions
a]
(S)-14
(S)-15
(S)-16
(R)-17
(R)-17
(R)-17
(R)-17
(S)(2R)-18a
(S)(2R)-19a
(S)(2R)-20a
(R)(2S)-21a
(R)(2S)-21a
(R)(2S)-21a
(R)(2S)-21a
65
54
77
83
87
66
34
95:5
93:7
88:12
93:7
93:7
93:7
93:7
[a]
[a]
[a]
2
3
4
5
6
7
II
that promote the hydrolysis and oxidation of the Ni com-
[
18]
plexes.
Consequently, drawing from our experience, we se-
[
[
d]
e]
lected the N-ethyl ligand 17 for a more detailed study. Our
choice was based not only on the optimal yield and diastereo-
selectivity obtained with 17 (Table 1, Entry 4) but also on its
lowest cost and molecular weight and as well as its attractive
physicochemical properties such as its solubility and the crystal-
linity of the target products 21. The options for the solvent and
base for these reactions are rather limited (Table S2), and we
conducted a brief study to optimize the stoichiometry. A com-
parable yield was obtained in the reaction when stoichiometric
[f]
[
a] Ligand (0.1 mmol), (rac)-4a (0.3 mmol), anhydrous Ni(OAc)
2
(0.2 mmol),
and KOtBu (1 mmol) in methanol (2 mL) were heated under reflux at 80 °C
for 8 h. [b] The combined yield of the isolated major and minor nickel com-
plexes. [c] The dr values were determined by HPLC analysis of the crude
reaction mixtures. [d] The same conditions as [a], except Ni(OAc)
was used. [e] The same conditions as [a], except (rac)-4a (0.2 mmol) was used.
f] The same conditions as [a], except (rac)-4a (0.1 mmol) was used.
2
(0.1 mmol)
[
amounts of ligand 17 and Ni(OAc) were used (Table 1, Entry 4
2
vs. 5). On the other hand, the reduction of the amount of 4a the chemical yield (Table 1, Entry 5 vs. 6 and 7). The absolute
from 3 equiv. to only 1 equiv. resulted in a gradual decrease in configuration of the major diastereoisomer (R,2S)-21a was de-
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termined by its disassembly and the isolation of enantiomeri- butyl (Table 2, Entry 14) groups, all of which reacted readily
[
19]
cally pure ꢀ-AA (S)-4a.
with ligand 17 to afford diastereomers 21l–21n with excellent
3
The optimized reaction conditions (Table S2) presented in stereochemical outcomes. Importantly, ꢀ -AA side chains with
Table 1, Entry 5 were used to study the substrate generality of increased steric bulk (Table 2, Entries 15–18) were perfectly
II
this method for the preparation of various enantiomerically compatible with the formation of the corresponding Ni com-
3
pure ꢀ -AAs through the reactions of ligand 17 with the corre- plexes, and derivatives 21o–21r (Table 2, Entries 15–18) were
3
sponding racemic ꢀ -AAs 4. The main results are collected in prepared with the excellent yields and diastereomeric preferen-
Table 2.
ces generally observed in these reactions. Finally, we prepared
compound 21s, which features a pharmacophoric 2,4,5-tri-
fluorobenzyl group, in an isolated yield of 87 % and a diastereo-
meric ratio (dr) of 95:5 (Table 2, Entry 19). One might agree
that these examples convincingly underscore the rather wide
generality of this approach for the preparation of various enan-
tiomerically pure ꢀ-substituted-ꢀ-amino acids from unprotected
Table 2. Substrate generality study of the reaction of ligand 17 with racemic
3
[a]
ꢀ
-AAs 4.
3
racemic ꢀ -AA 4.
To gain a more detailed view of the process, we conducted
analysis (HPLC) of the progress and diastereoselectivity of the
reaction of (R)-17 with (rac)-4a over time (Figure 1, Table S3).
II
Yield [%][b]
dr[c]
Entry Ni complex
R
1[d]
2
3
4
5
6
7
8
9
(R)(2S)-21a
(R)(2S)-21b
(R)(2S)-21c
(R)(2S)-21d
(R)(2S)-21e
(R)(2S)-21f
(R)(2S)-21g
(R)(2S)-21h
(R)(2S)-21i
(R)(2S)-21j
(R)(2S)-21k
(R)(2R)-21l
(R)(2R)-21m
(R)(2R)-21n
(R)(2R)-21o
(R)(2S)-21p
(R)(2S)-21q
(R)(2S)-21r
(R)(2R)-21s
phenyl
2-F-phenyl
4-Cl-phenyl
3,4-diOMe-phenyl
4-isopropylphenyl
4-OMe-phenyl
3-OMe-phenyl
3
3-CF -phenyl
3-pyridyl
2-thienyl
2-naphthyl
methyl
ethyl
n-butyl
87
92
93
93
92
93
90
50
80
95
91
87
94
97
91
76
93
85
87
93:7
89:11
92:8
93:7
93:7
88:12
90:10
96:4
98:2
98:2
92:8
90:10
96:4
94:6
92:8
95:5
98:2
94:6
95:5
10
11
12
13
14
15
16
17
18
19
Figure 1. Progress and diastereoselectivity of the reaction of (R)-17 with (rac)-
isobutyl
4a over time.
isopropyl
cyclopropyl
cyclohexyl
2,4,5-trifluorobenzyl
As shown in Figure 1, (R)-17 reacts preferentially with the (S)-
enantiomer of AA 4a to afford diastereomers (R)(2S)-21a/
(R)(2R)-21a in ca. 60:20 ratio at the point of 80 % consumption.
The following observations are quite interesting and important
for understanding the process under study. First, the proportion
of the minor diastereomer (R)(2R)-21a reaches ca. 20 % in the
early stages of the reaction and then gradually decreases to
less than 10 %. Second, the amount of the major product
[
a] Reaction conditions: (R)-17 (0.1 mmol), (rac)-4 (0.3 mmol), anhydrous
Ni(OAc) (0.1 mmol), and KOtBu (1 mmol) in methanol (2 mL) were heated
under reflux at 80 °C for 8 h. [b] The combined yield of the isolated products
R)(2S)-21 and (R)(2R)-21. [c] The dr values were determined by HPLC analysis
of the crude reaction mixtures. [d] Large-scale synthesis with (R)-17
13.48 mmol).
2
(
(
For the series of ꢀ-phenyl-substituted racemates 4a–4h, the (R)(2S)-21a progressively increases to over 80 %. Third, the
corresponding diastereomers 21a–21h were obtained with av- minor diastereomer (R)(2R)-21a is probably thermodynamically
erage chemical yields of ca. 90 % and strong diastereomeric unstable and undergoes gradual epimerization into the major
preferences of more than 90:10 on average (Table 2, Entries 1– product (R)(2S)-21a. To validate this assumption, we conducted
8
). The presence of halogen atoms (Table 2, Entries 2 and 3) or a special epimerization experiment, as presented in Scheme 3.
alkyl (Table 2, Entry 5), methoxy (Table 2, Entries 4, 6, and 7), Thus, the minor product (R)(2R)-21f was obtained in dia-
and trifluoromethyl (Table 2, Entry 8) groups did not show any stereomerically pure form by column chromatography and ex-
noticeable influence on the stereochemical outcomes of these posed to the standard reaction conditions. As is evident form
3
reactions. Racemic ꢀ -AAs 4i–4k containing heterocyclic moie- this epimerization experiment, minor diastereomer (R)(2R)-21f
ties, such as pyridyl (Table 2, Entry 9), thienyl (Table 2, Entry 10), is indeed thermodynamically unstable and undergoes gradual
or naphthyl (Table 2, Entry 11) groups, reacted with ligand 17 transformation into the major product (R)(2S)-21f. It is quite
without any complications to furnish products 21i–21k with reasonable to assume that the deprotonated ꢀ-carbanion A can
excellent yields and diastereomeric ratios. In the aliphatic series, be efficiently stabilized through the formation of the dibenzylic
we first studied racemates 4l–4n bearing straight chains such anion B, which might be further stabilized by the delocalization
as methyl (Table 2, Entry 12), ethyl (Table 2, Entry 13), and n- of the negative charge onto two phenyl rings. This mode of ꢀ-
Eur. J. Org. Chem. 2018, 1821–1832
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Scheme 3. Epimerization of the thermodynamically unstable minor diastereomer (R)(2R)-21f to the major diastereomer (R)(2S)-21f.
anion stabilization can explain the relatively high C–H acidity of (R)(2S)-21a was repeated on a large scale (13.48 mmol), and
the ꢀ-carbon atom and the concomitant epimerization. One it was purified to a diastereomerically pure state by column
may agree that all of these data point to the possibility of the chromatography. As shown in Scheme 4, the disassembly of
II
dynamic resolution that we observe in this process.
Ni complex (R)(2S)-21a was conducted under the usual acidic
In the final part of this work, we disassembled the major conditions to afford the target AA (S)-4a. After the Boc-protec-
diastereomer (R)(2S)-21a and used the isolated enantiomerically tion of (S)-4a in quantitative yield, acid (S)-22 was subjected
3
pure ꢀ -AA 4a for the synthesis of the antiretroviral drug mara- to a reduction reaction with BH
·THF (THF = tetrahydrofuran),
3
[
20]
viroc.
To this end, the synthesis of the major diastereomer followed by Dess–Martin oxidation to obtain aldehyde (S)-24 in
3
Scheme 4. Disassembly of major diastereomer (R)(2S)-21a, isolation of free enantiomerically pure ꢀ -AA 4a, and the synthesis of maraviroc (S)-29.
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1
an overall yield of 95 %. Then, the reductive amination reaction to give product (S)-11 (12 g, 62 % yield). H NMR {500 MHz, [D
]di-
6
methyl sulfoxide ([D ]DMSO)}: δ = 10.39 (s, 1 H), 8.02 (d, J = 8.9 Hz,
between (S)-24 and amine 25 was conducted to afford (S)-26
in 71 % yield. Finally, after Boc-deprotection, the condensation
between amine (S)-27 and acid 28 in the presence of 1-ethyl-
6
1
7
1
H), 7.76–7.71 (m, 1 H), 7.70–7.63 (m, 3 H), 7.54 (t, J = 7.7 Hz, 2 H),
.46 (d, J = 2.6 Hz, 1 H), 3.64–3.50 (m, 1 H), 3.42–3.38 (m, 1 H), 1.79–
.62 (m, 4 H), 1.39 (s, 3 H), 1.26 (s, 9 H) ppm.
3-(3-dimethylaminopropyl)carbodiimide (EDCI) and hydroxy-
benzotriazole (HOBT) was performed to successfully afford (S)-N-(2-Benzoyl-4-chlorophenyl)-2-methylpyrrolidine-2-carb-
maraviroc (S)-29 in 75 % yield with high enantiomeric purity oxamide [(S)-12]: (S)-11 (8.5 g, 19.19 mmol) was dissolved in DCM
(
20 mL), and then trifluoroacetic acid (TFA, 20 mL) was added. The
reaction mixture was stirred for 4 h and distilled in vacuo to give
S)-N-(2-benzoyl-4-chlorophenyl)-2-methylpyrrolidine-2-carbox-
(
>98.2 % ee).
(
1
amide [(S)-12] as a light yellow solid (6.5 g, yield 98 %). H NMR
500 MHz, CDCl ): δ = 11.95 (s, 1 H), 8.63 (d, J = 8.9 Hz, 1 H), 7.78–
Conclusions
(
3
We have developed a purely chemical method for the resolu- 7.72 (m, 2 H), 7.66–7.56 (m, 1 H), 7.54–7.44 (m, 4 H), 3.16 (dt, J =
3
10.6, 6.4 Hz, 1 H), 3.00–2.91 (m, 1 H), 2.35–2.24 (m, 1 H), 1.82–1.63
tion of unprotected racemic ꢀ -AAs that uses specially de-
(
m, 4 H), 1.46 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl ): δ = 196.9,
signed, stable, and recyclable ligands. The new ligands have
better thermodynamic stabilities than those we used previ-
ously. The methods showed a broad synthetic generality for
various substituted ꢀ -AAs. Furthermore, the presented method (S)-N-(2-Benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-meth-
has an excellent stereochemical outcome, a fully recyclable ylpyrrolidine-2-carboxamide [(S)-14]: (S)-12 (5 g, 14.58 mmol),
source of chirality, and involves operationally simple and conve- 3,4-dichlorobenzaldehyde (13a, 2.81 g, 16.04 mmol) were dissolved
in 1,2-dichloroethane (DCE, 15 mL), and AcOH (cat. amount) was
nient reaction conditions that allow its scalability. Furthermore,
we successfully applied the method to obtain the essential in-
3
1
1
77.4, 137.9, 137.9, 133.2, 132.9, 131.8, 130.1, 128.5, 127.3, 126.7,
22.8, 67.4, 47.2, 38.1, 26.5, 25.8 ppm.
3
added. The resulting mixture was stirred at room temperature for
0.5 h. Sodium triacetoxyborohydride (4.64 g, 21.88 mmol) was
added, and the solution was stirred overnight. The reaction was
3
termediate ꢀ -AA in the synthesis of the anti-HIV drug maravi-
roc in an overall yield of 49 %, which possibly makes it of great
interest to industry.
terminated with NaHCO (20 mL). The mixture was extracted with
3
dichloromethane (10 mL × 3). The combined organic layers were
dried with Na SO , concentrated, and purified by silica gel column
2
4
chromatography (petroleum ether/ethyl acetate 4:1) to give the
Experimental Section
product (S)-14 as a white solid (7 g, yield 95 %). M.p. 110–111 °C.
2
0
1
[
α] = –22.54 (c = 0.1, CHCl ). H NMR (400 MHz, CDCl ): δ = 11.76
D
3
3
General Information: The commercially available chemicals were
used without further purification. Anhydrous nickel acetate was pre-
pared by heating reagent-grade nickel acetate tetrahydrate for 2 h
at 110 °C under vacuum. The H and C NMR spectra were re-
corded at 400 MHz or 500 MHz with a Bruker AV400 instrument.
The chemical shifts are reported in parts per million (ppm) down-
field from tetramethylsilane. The proton coupling patterns are de-
scribed as singlet (s), doublet (d), triplet (t), quartet (q), multiplet
(
s, 1 H), 8.65 (d, J = 8.7 Hz, 1 H), 7.86–7.40 (m, 8 H), 7.22–7.13 (m, 2
H), 3.79 (d, J = 13.5 Hz, 1 H), 3.39 (d, J = 13.6 Hz, 1 H), 3.15 (t, J =
7
1
1
1
4
.4 Hz, 1 H), 2.39 (dd, J = 15.9, 7.9 Hz, 1 H), 2.23–2.14 (m, 1 H), 1.95–
1
13
.75 (m, 3 H), 1.39 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl ): δ =
3
97.1, 176.5, 139.2, 138.4, 137.9, 133.4, 132.9, 132.3, 132.2, 130.8,
30.6, 130.1, 130.1, 128.5, 127.9, 127.2, 125.9, 122.8, 68.8, 53.5, 51.3,
0.1, 22.7, 16.4 ppm. MS (ESI+, APCI): m/z = 501.1. HRMS (ESI): calcd.
+
+
for C H Cl N O [M + H] 501.0898; found 501.0900.
26
23
3 2 2
(m), and broad (br). The high-resolution mass spectroscopy (HRMS)
was performed with a Micromass Ultra Q-TOF spectrometer. The
determination of the dr values was performed by HPLC or LC–MS
analysis with an Agilent 1260 Infinity spectrometer. The optical rota-
(
2
7
S)-N-(2-Benzoyl-4-chlorophenyl)-1-benzyl-2-methylpyrrolidine-
-carboxamide [(S)-15]: White solid (3 g, yield 96 %). M.p. 72–
20
1
3 °C. [α]D = –127.1 (c = 0.118, CHCl ). H NMR (500 MHz, CDCl ):
3
3
tions were measured with a 1 mL cell with a 1 dm path length with
δ = 11.52 (s, 1 H), 8.58 (d, J = 8.9 Hz, 1 H), 7.78–7.73 (m, 2 H), 7.66–
7.60 (m, 1 H), 7.53–7.43 (m, 4 H), 7.35–7.28 (m, 2 H), 7.15–7.03 (m,
3
D
an Autopol VI automatic polarimeter, and the [α]2 values are re-
0
ported as follows (c [g/100 mL], solvent).
H), 3.79 (d, J = 13.0 Hz, 1 H), 3.40 (d, J = 13.1 Hz, 1 H), 3.18–3.04
(
m, 1 H), 2.45–2.35 (m, 1 H), 2.20–2.10 (m, 1 H), 1.86–1.70 (m, 3 H),
General Procedure
1
1
1
.39 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl ): δ = 196.7, 176.9, 138.9,
3
tert-Butyl (S)-2-[(2-Benzoyl-4-chlorophenyl)carbamoyl]-2-meth-
ylpyrrolidine-1-carboxylate [(S)-11]: (S)-1-(tert-Butoxycarbonyl)-2-
methylpyrrolidine-2-carboxylic acid (10, 10 g, 43.62 mmol), 1-
methyl-1H-imidazole (10.33 mL, 130.85 mmol), and 4-dimethyl-
aminopyridine (DMAP, cat.) were dissolved in anhydrous dichloro-
methane (DCM, 200 mL), and the mixture was cooled to 0 °C
under N2 protection. Methanesulfonyl chloride (MsCl, 4.05 mL,
38.0, 137.9, 133.1, 133.1, 131.6, 130.2, 128.7, 128.3, 127.4, 127.0,
27.0, 123.0, 68.7, 54.4, 51.3, 40.4, 22.9, 16.5 ppm. MS (ESI+, APCI):
+
+
m/z = 433.1. HRMS (ESI): calcd. for C H ClN O [M + H] 433.1677;
found 433.1682.
26
25
2 2
(S)-N-(2-Benzoyl-4-chlorophenyl)-2-methyl-1-(3-phenyl-
propyl)pyrrolidine-2-carboxamide [(S)-16]: Yellow oil (4 g, yield
92 %). [α] = –95.0 (c = 0.1, CHCl ). H NMR (500 MHz, CDCl ): δ =
2
0
1
5
2.34 mmol) was added with a syringe. After 15 min, a solution of
D
3
3
(
2-amino-5-chlorophenyl)(phenyl)methanone (8, 11.12 g, 47.98 mmol)
11.60 (s, 1 H), 8.57 (d, J = 9.0 Hz, 1 H), 7.73 (d, J = 7.6 Hz, 2 H), 7.60
(t, J = 7.4 Hz, 1 H), 7.52–7.40 (m, 4 H), 7.17–7.05 (m, 3 H), 6.96 (d,
J = 6.7 Hz, 2 H), 3.41–3.31 (m, 1 H), 2.55–2.33 (m, 5 H), 2.14–2.06
in DCM (40 mL) was added with a syringe. The reaction mixture
was stirred at 5 °C overnight. Once the condensation was complete,
as determined by TLC (petroleum ether/ethyl ester 8:1), saturated
1
3
(m, 1 H), 1.93 (s, 1 H), 1.86–1.69 (m, 4 H), 1.24 (s, 3 H) ppm. C NMR
NH Cl(aq) was added to the reaction mixture, which was extracted
(125 MHz, CDCl ): δ = 196.6, 177.4, 142.1, 138.0, 137.9, 133.1, 131.6,
4
3
three times with CH Cl . The combined organic layers were dried
130.2, 128.6, 128.3, 128.3, 127.3, 127.0, 125.7, 123.1, 68.6, 51.5, 49.9,
2
2
with Na SO and then concentrated in vacuo. The residue was puri-
fied by flash column chromatography (silica gel, EtOAc/hexane 1:20)
40.4, 33.9, 30.9, 22.9, 16.3 ppm. MS (ESI+, APCI): m/z = 461.1. HRMS
2
4
+
+
(ESI): calcd. for C H ClN O [M + H] 461.1990; found 461.1989.
28 29 2 2
Eur. J. Org. Chem. 2018, 1821–1832
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1826
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(
2
8
R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methylpyrrolidine-
-carboxamide [(R)-17]: Yellow solid (10 g, yield 95 %). M.p. 87–
1 H), 2.15 (td, J = 12.3, 11.8, 4.3 Hz, 1 H), 1.96–1.84 (m, 1 H), 1.78–
1.66 (m, 1 H), 1.61–1.54 (m, 1 H), 1.53–1.43 (m, 1 H), 1.02 (s, 3 H)
2
0
1
13
8 °C. [α]D = +143.5 (c = 0.108, CHCl ). H NMR (500 MHz, CDCl ):
ppm. C NMR (125 MHz, [D ]methanol): δ = 183.3, 177.0, 173.5,
3
3
4
δ = 11.62 (s, 1 H), 8.60 (d, J = 9.0 Hz, 1 H), 7.75 (d, J = 7.2 Hz, 2 H),
142.5, 142.3, 140.9, 136.1, 134.0, 133.5, 131.6, 131.4, 130.8, 130.6,
130.4, 129.6, 129.4, 129.4, 128.5, 128.4, 127.8, 127.1, 126.9, 126.4,
75.5, 64.0, 55.1, 53.5, 40.9, 38.3, 34.7, 32.0, 21.5, 17.7 ppm. MS (ESI+,
APCI): m/z = 664.2. HRMS (ESI): calcd. for C H ClN NiO [M + H]+
7
1
2
.61 (t, J = 7.4 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 3 H), 7.42 (d, J = 2.5 Hz,
H), 3.39–3.32 (m, 1 H), 2.57–2.45 (m, 1 H), 2.43–2.32 (m, 2 H), 2.14–
.03 (m, 1 H), 1.78–1.67 (m, 3 H), 1.25 (s, 3 H), 1.10 (t, J = 7.2 Hz, 3
+
37
36
3
3
13
H) ppm. C NMR (125 MHz, CDCl ): δ = 196.5, 177.5, 137.9, 137.9,
644.1871; found 664.1884.
3
1
4
33.1, 133.0, 131.5, 130.1, 128.6, 127.2, 127.1, 122.9, 68.4, 51.0, 43.9,
0.5, 22.8, 16.2, 14.5 ppm. MS (ESI+, APCI): 371.1. HRMS (ESI): calcd.
Nickel(II) (R)-N-(2-benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-phenylpropanoic
Acid Schiff Base Complex [(R)(2S)-21a]: (R)-17 (5 g, 13.48 mmol),
3-amino-3-phenylpropanoic acid (4a, 6.68 g, 40.44 mmol), and
+
+
for C H ClN O [M + H] 371.1521; found 371.1527.
21
23
2 2
Nickel(II) (S)-(2-Benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-
-methylpyrrolidine-2-carboxamide/(R)-3-amino-3-phenyl-
propanoic Acid Schiff Base Complex [(S)(2R)-18a]: (S)-14
2
Ni(OAc) (4.77 g, 26.96 mmol), were dissolved in MeOH (200 mL),
2
and KOtBu (15.13 g, 134.82 mmol) was added. The mixture was
(
50.20 mg, 0.10 mmol), 3-amino-3-phenylpropanoic acid (4a,
heated under reflux at 80 °C for 8 h, and then the reaction was
4
9.57 mg, 0.30 mmol), and Ni(OAc)2 (35.37 mg, 0.20 mmol) were terminated by the addition of ice water/5 % acetic acid (200 mL).
The mixture was extracted with dichloromethane (100 mL × 3). The
added. The resulting mixture was heated under reflux at 80 °C for combined organic layers were dried with Na SO , concentrated for
dissolved in MeOH (2 mL), and KOtBu (112.25 mg, 1.00 mmol) was
2
4
8
5
h. The reaction was terminated by the addition of ice water with analysis (dr = 93:7), and purified to give the crude products 21a
% acetic acid (10 mL). The mixture was extracted with DCM (6.8 g, yield 87 %). The crude product was further purified by silica
(
10 mL × 3). The combined organic layers were dried with Na SO ,
gel column chromatography (dichloromethane/methanol 40:1) to
2
4
concentrated for analysis (dr = 95:5), and purified to give the crude
products 18a (46 mg, yield 65 %). The crude product was purified
by silica gel column chromatography (dichloromethane/methanol
give the major pure diastereomer (R)(2S)-21a as a brown solid. M.p.
2
0
1
174–176 °C. [α] = –2531.8 (c = 0.044, CHCl ). H NMR (400 MHz,
D
3
[D ]methanol): δ = 8.18 (d, J = 9.1 Hz, 1 H), 7.71–7.46 (m, 9 H), 7.31
4
4
0:1) to give the major pure diastereomer (S)(2R)-18a as a brown
(dd, J = 9.1, 2.6 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 6.72 (d, J = 2.6 Hz,
2
0
solid (45.8 mg, yield 65 %). M.p. 160–162 °C. [α] = +1892.1 (c = 1 H), 4.60 (d, J = 3.7 Hz, 1 H), 3.23 (td, J = 12.3, 11.3, 7.1 Hz, 1 H),
0
2
7
1
1
2
D
.038, CHCl3). 1H NMR (500 MHz, [D ]methanol): δ = 8.89 (d, J =
2.93 (dd, J = 17.8, 2.8 Hz, 1 H), 2.80 (t, J = 9.2 Hz, 1 H), 2.69 (dd, J =
17.8, 4.1 Hz, 1 H), 2.40 (dq, J = 14.5, 7.3 Hz, 1 H), 2.23 (dq, J = 13.8,
6.9 Hz, 1 H), 2.02–1.91 (m, 1 H), 1.87 (t, J = 7.3 Hz, 3 H), 1.80–1.45
4
.1 Hz, 1 H), 8.34 (dd, J = 8.2, 2.1 Hz, 1 H), 7.83 (d, J = 9.2 Hz, 1 H),
.69–7.42 (m, 10 H), 7.10 (dd, J = 9.2, 2.6 Hz, 1 H), 7.06 (d, J = 7.7 Hz,
H), 6.60 (d, J = 2.6 Hz, 1 H), 4.51 (t, J = 3.5 Hz, 1 H), 3.59 (d, J =
3.3 Hz, 1 H), 3.29–3.21 (m, 2 H), 2.97 (dd, J = 17.9, 2.8 Hz, 1 H),
.92–2.85 (m, 1 H), 2.63 (dd, J = 17.9, 4.2 Hz, 1 H), 2.05–1.95 (m, 1
(m, 3 H), 1.10 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl ): δ = 182.1,
3
172.8, 171.3, 142.0, 139.8, 134.9, 133.0, 132.9, 130.5, 130.0, 129.9,
129.5, 129.4, 128.5, 127.3, 126.9, 126.6, 125.6, 125.3, 73.3, 63.1, 53.5,
49.1, 40.5, 38.2, 20.3, 17.3, 15.3 ppm. MS (ESI+, APCI): m/z = 574.1.
13
H), 1.86–1.78 (m, 1 H), 1.74–1.55 (m, 2 H), 1.30 (s, 3 H) ppm.
NMR (125 MHz, [D ]methanol): δ = 182.6, 176.7, 173.4, 141.9, 140.9, HRMS (ESI): calcd. for C H ClN NiO [M + H] 574.1402; found
C
+
+
4
30 30
3
3
1
1
5
38.3, 136.1, 134.5, 134.0, 133.7, 133.4, 133.1, 132.5, 132.2, 131.6, 574.1405.
30.8, 130.6, 130.4, 129.7, 128.4, 128.2, 127.8, 126.9, 126.0, 74.8, 63.8,
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-(2-fluorophenyl)-
propanoic Acid Schiff Base Complex [(R)(2S)-21b]: Brown solid
6.5, 54.6, 42.2, 38.6, 20.5, 18.4 ppm. MS (ESI+, APCI): m/z = 704.0.
HRMS (ESI): calcd. for C H Cl N NiO [M + H]+ 704.0779; found
+
3
5
30
3
3
3
7
04.0783.
2
0
(54.5 mg, yield 92 %, dr 89:11). M.p. 180–181 °C. [α] = –3281.3 (c =
D
1
Nickel(II) (S)-N-(2-Benzoyl-4-chlorophenyl)-1-benzyl-2-methyl-
0.048, CHCl3). H NMR (400 MHz, [D ]methanol): δ = 8.21 (d, J =
4
pyrrolidine-2-carboxamide/(R)-3-amino-3-phenylpropanoic 9.1 Hz, 1 H), 7.69–7.50 (m, 5 H), 7.45–7.35 (m, 3 H), 7.30 (dd, J = 9.1,
Acid Schiff Base Complex [(S)(2R)-19a]: Brown solid (34.3 mg, 2.6 Hz, 1 H), 7.12–7.05 (m, 1 H), 6.65 (d, J = 2.6 Hz, 1 H), 4.71 (t, J =
yield 54 %). M.p. 160–161 °C. [α]D = +2822.7 (c = 0.044, CHCl ). H 3.3 Hz, 1 H), 3.26–3.14 (m, 1 H), 2.93–2.82 (m, 2 H), 2.73 (dd, J =
2
0
1
3
NMR (500 MHz, [D ]methanol): δ = 8.52 (d, J = 7.6 Hz, 2 H), 7.83–
18.0, 4.4 Hz, 1 H), 2.44–2.33 (m, 1 H), 2.30–2.18 (m, 1 H), 2.04–1.92
(m, 1 H), 1.90–1.78 (m, 4 H), 1.75–1.55 (m, 2 H), 1.09 (s, 3 H) ppm.
4
6
(
.98 (m, 15 H), 6.59 (d, J = 2.6 Hz, 1 H), 4.52 (t, J = 3.6 Hz, 1 H), 3.56
d, J = 13.1 Hz, 1 H), 3.42–3.27 (m, 2 H), 2.97–2.81 (m, 2 H), 2.60 (dd,
J = 17.8, 4.2 Hz, 1 H), 2.07–1.95 (m, 1 H), 1.85–1.55 (m, 3 H), 1.33 (s,
13
C NMR (150 MHz, CDCl ): δ = 181.5, 171.7, 162.0, 142.1, 135.1,
3
133.1, 132.9, 131.0, 130.5, 130.2, 129.6, 128.8, 128.7, 128.6, 127.3,
127.3, 126.5, 125.4, 125.1, 124.8, 116.7, 116.5, 73.7, 60.0, 53.2, 49.2,
3
1
1
7
H) ppm. 13C NMR (125 MHz, [D ]methanol): δ = 182.9, 176.8, 173.3,
4
42.2, 140.9, 137.2, 136.2, 133.4, 132.8, 132.5, 131.5, 130.8, 130.8, 40.6, 38.9, 20.7, 16.7, 15.2 ppm. MS (ESI+, APCI): m/z = 592.2. HRMS
30.6, 130.3, 130.2, 129.6, 129.5, 128.4, 128.3, 127.7, 126.9, 126.5, (ESI): calcd. for C30H29ClFN NiO3 [M + H] 592.1308; found
5.1, 63.8, 58.3, 54.4, 42.2, 38.5, 20.7, 18.3 ppm. MS (ESI+, APCI):
+
+
3
592.1311.
+
+
m/z = 636.2. HRMS (ESI): calcd. for C35H32ClN NiO [M + H]
3
3
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-(4-chlorophenyl)-
6
36.1558; found 636.1573.
Nickel(II) (S)-N-(2-Benzoyl-4-chlorophenyl)-2-methyl-1-(3- propanoic Acid Schiff Base Complex [(R)(2S)-21c]: Brown solid
2
0
phenylpropyl)pyrrolidine-2-carboxamide/(R)-3-amino-3-phen-
ylpropanoic Acid Schiff Base Complex [(S)(2R)-20a]: Brown solid
(56.5 mg, yield 93 %, dr 92:8). M.p. 180–182 °C. [α] = –3512.5 (c =
D
0.04, CHCl3). 1H NMR (500 MHz, [D ]methanol): δ = 8.19 (d, J =
51.1 mg, yield 77 %). M.p. 135–137 °C. [α] = +2582.6 (c = 0.046, 9.1 Hz, 1 H), 7.68–7.47 (m, 8 H), 7.31 (dd, J = 9.1, 2.6 Hz, 1 H), 7.21
4
2
0
(
D
1
CHCl ). H NMR (500 MHz, [D ]methanol): δ = 8.02 (d, J = 9.0 Hz, 1
(dt, J = 7.6, 1.5 Hz, 1 H), 6.71 (d, J = 2.6 Hz, 1 H), 4.57 (t, J = 3.3 Hz,
1 H), 3.30–3.21 (m, 1 H), 2.90 (dd, J = 17.9, 2.8 Hz, 1 H), 2.86–2.79
(m, 1 H), 2.70 (dd, J = 17.9, 4.1 Hz, 1 H), 2.46–2.37 (m, 1 H), 2.28–
3
4
H), 7.73–7.41 (m, 9 H), 7.32–7.05 (m, 7 H), 6.71 (d, J = 2.6 Hz, 1 H),
4
2
.58 (t, J = 3.4 Hz, 1 H), 3.24 (td, J = 12.3, 5.3 Hz, 1 H), 3.12–2.98 (m,
H), 2.92 (dd, J = 17.8, 2.8 Hz, 1 H), 2.84–2.73 (m, 2 H), 2.69 (dd, 2.19 (m, 1 H), 2.07–1.99 (m, 1 H), 1.88 (t, J = 7.3 Hz, 3 H), 1.85–1.77
(m, 1 H), 1.75–1.63 (m, 1 H), 1.61–1.52 (m, 1 H), 1.12 (s, 3 H) ppm.
J = 17.8, 4.2 Hz, 1 H), 2.60–2.46 (m, 1 H), 2.31 (td, J = 12.4, 5.0 Hz,
Eur. J. Org. Chem. 2018, 1821–1832
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1827
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
13
C NMR (125 MHz, [D ]Methanol): δ = 183.6, 176.7, 173.8, 142.6,
(125 MHz, [D ]methanol): δ = 183.6, 177.0, 173.4, 162.1, 142.6, 142.4,
4
4
1
1
2
39.8, 136.1, 135.6, 134.1, 133.5, 131.6, 131.2, 130.8, 130.6, 130.4, 136.1, 134.1, 133.5, 131.9, 131.6, 131.4, 130.8, 130.4, 128.4, 128.4,
29.6, 128.4, 128.3, 126.9, 126.6, 75.0, 63.5, 53.7, 50.2, 41.3, 38.3,
126.9, 126.6, 119.9, 114.4, 114.1, 75.1, 64.0, 55.9, 53.6, 50.2, 41.0,
1.4, 17.7, 15.5 ppm. MS (ESI+, APCI): m/z = 608.1. HRMS (ESI): calcd.
38.4, 21.4, 17.7, 15.5 ppm. MS (ESI+, APCI): m/z = 604.1. HRMS (ESI):
+
+
+
+
for C H Cl N NiO [M + H] 608.1012; found 608.1027.
calcd. for C H ClN NiO [M + H] 604.1508; found 604.1518.
30
29
2
3
3
31 32 3 4
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-(3,4-dimethoxy-
phenyl)propanoic Acid Schiff Base Complex [(R)(2S)-21d]: Brown
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-(3-(trifluoromethyl)-
phenyl)propanoic Acid Schiff Base Complex [(R)(2S)-21h]: Brown
2
0
20
solid (59.0 mg, yield 93 %, dr 93:7). M.p. 160–162 °C. [α] = –2768.3 solid (32.1 mg, yield 50 %, dr 96:4). M.p. 158–160 °C. [α] = –3280.6
D
D
1
1
(
c = 0.06, CHCl ). H NMR (400 MHz, [D ]methanol): δ = 8.16 (d, J = (c = 0.036, CHCl ). H NMR (500 MHz, [D ]methanol): δ = 8.19 (d,
3
4
3
4
9
.1 Hz, 1 H), 7.67–7.50 (m, 4 H), 7.32 (dd, J = 9.1, 2.6 Hz, 1 H), 7.24
J = 9.2 Hz, 1 H), 7.86 (dd, J = 28.1, 4.2 Hz, 3 H), 7.69–7.50 (m, 5 H),
7.33 (dd, J = 9.1, 2.7 Hz, 1 H), 7.18 (d, J = 7.7 Hz, 1 H), 6.73 (d, J =
2.6 Hz, 1 H), 4.68 (t, J = 3.3 Hz, 1 H), 3.24–3.12 (m, 1 H), 2.98 (dd,
J = 18.0, 2.9 Hz, 1 H), 2.87–2.73 (m, 2 H), 2.45–2.19 (m, 2 H), 2.06–
(d, J = 8.4 Hz, 1 H), 7.20–7.13 (m, 1 H), 7.09–7.03 (m, 1 H), 6.89 (d,
J = 2.2 Hz, 1 H), 6.71 (d, J = 2.6 Hz, 1 H), 4.56 (t, J = 3.4 Hz, 1 H),
3
.93 (s, 3 H), 3.82 (s, 3 H), 3.27–3.16 (m, 1 H), 2.94–2.79 (m, 2 H),
2
.67 (dd, J = 17.8, 4.1 Hz, 1 H), 2.46–2.35 (m, 1 H), 2.31–2.21 (m, 1
1.94 (m, 1 H), 1.88 (t, J = 7.3 Hz, 3 H), 1.72–1.48 (m, 3 H), 1.12 (s, 3
13
13
H), 2.04–1.81 (m, 5 H), 1.72–1.50 (m, 2 H), 1.12 (s, 3 H) ppm.
C
H) ppm. C NMR (125 MHz, [D ]methanol): δ = 183.6, 176.6, 174.2,
4
NMR (125 MHz, CDCl ): δ = 182.0, 172.9, 171.0, 149.7, 149.4, 142.0,
142.7, 142.4, 136.0, 134.2, 133.7, 132.8, 132.6, 132.2, 131.7, 131.7,
3
1
1
4
35.0, 133.0, 132.9, 132.5, 130.5, 130.0, 129.9, 129.4, 127.2, 126.7, 131.2, 130.9, 130.5, 128.4, 128.2, 127.0, 126.6, 126.5, 123.9, 75.0, 63.6,
25.7, 125.3, 119.6, 112.0, 110.0, 73.4, 62.9, 56.4, 56.3, 53.4, 49.1,
53.5, 50.2, 41.1, 38.3, 21.4, 17.7, 15.5 ppm. MS (ESI+, APCI): m/z =
+
+
0.4, 38.4, 20.5, 17.3, 15.3 ppm. MS (ESI+, APCI): m/z = 634.2. HRMS
642.1. HRMS (ESI): calcd. for C H ClF N NiO [M + H] 642.1276;
31 29 3 3 3
+
+
(ESI): calcd. for C H ClN NiO [M + H] 634.1613; found 634.1627. found 642.1268.
32 34 3 5
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-(4-isopropylphenyl)-
propanoic Acid Schiff Base Complex [(R)(2S)-21e]: Brown solid
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-(pyridin-3-yl)propan-
oic Acid Schiff Base Complex [(R)(2S)-21i]: Brown solid (46.0 mg,
2
0
20
(
0
9
56.7 mg, yield 92 %, dr 93:7). M.p. 120–122 °C. [α] = –2287.5 (c =
yield 80 %, dr 98:2). M.p. 138–140 °C. [α] = –2835.4 (c = 0.048,
D
D
.048, CHCl3). 1H NMR (400 MHz, [D ]methanol): δ = 8.17 (d, J =
CHCl ). H NMR (400 MHz, [D ]methanol): δ = 8.78 (d, J = 2.5 Hz, 1
1
4
3
4
.2 Hz, 1 H), 7.66–7.47 (m, 6 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.31 (dd,
H), 8.76 (dd, J = 4.6, 1.4 Hz, 1 H), 8.19 (d, J = 9.2 Hz, 1 H), 8.00–7.92
(m, 1 H), 7.75–7.51 (m, 5 H), 7.33 (dd, J = 9.2, 2.6 Hz, 1 H), 7.24 (d,
J = 7.7 Hz, 1 H), 6.72 (d, J = 2.6 Hz, 1 H), 4.70 (t, J = 3.6 Hz, 1 H),
J = 9.1, 2.6 Hz, 1 H), 7.22–7.16 (m, 1 H), 6.72 (d, J = 2.6 Hz, 1 H),
.56 (d, J = 3.5 Hz, 1 H), 3.27–3.17 (m, 1 H), 3.10–2.98 (m, 1 H), 2.90
4
(dd, J = 17.8, 2.8 Hz, 1 H), 2.79 (t, J = 9.1 Hz, 1 H), 2.67 (dd, J = 17.8, 3.29–3.18 (m, 1 H), 2.99 (dd, J = 17.9, 2.9 Hz, 1 H), 2.87–2.73 (m, 2
4
.2 Hz, 1 H), 2.45–2.34 (m, 1 H), 2.28–2.17 (m, 1 H), 1.97–1.82 (m, 4 H), 2.44–2.25 (m, 2 H), 2.09–1.98 (m, 1 H), 1.88 (t, J = 7.3 Hz, 3 H),
H), 1.77–1.45 (m, 3 H), 1.34 (d, J = 6.9 Hz, 6 H), 1.10 (s, 3 H) ppm.
1.74–1.50 (m, 3 H), 1.13 (s, 3 H) ppm. 13C NMR (125 MHz, [D ]meth-
4
13
C NMR (125 MHz, CDCl ): δ = 182.0, 172.9, 171.1, 149.6, 142.0,
anol): δ = 183.4, 176.4, 174.4, 150.1, 148.6, 142.7, 137.7, 136.5, 136.0,
3
1
1
2
37.3, 135.0, 133.0, 132.9, 130.5, 130.0, 130.0, 129.4, 127.6, 127.4, 134.1, 133.7, 131.7, 131.1, 130.9, 130.5, 128.3, 128.3, 126.9, 126.6,
27.0, 126.7, 125.6, 125.3, 73.4, 62.9, 53.3, 49.1, 40.3, 38.1, 34.1, 24.3,
125.9, 75.1, 62.4, 53.4, 50.3, 41.1, 38.1, 21.4, 17.7, 15.5 ppm. MS
+
4.2, 20.4, 17.2, 15.3 ppm. MS (ESI+, APCI): m/z = 616.2. HRMS (ESI):
(ESI+, APCI): m/z = 575.1. HRMS (ESI): calcd. for C H ClN NiO [M
29
29
4
3
+
+
+
calcd. for C H ClN NiO [M + H] 616.1871; found 616.1886.
+ H] 575.1354; found 575.1347.
33
36
3
3
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-(4-methoxy-
phenyl)propanoic Acid Schiff Base Complex [(R)(2S)-21f]: Brown
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-(thiophen-2-yl)-
propanoic Acid Schiff Base Complex [(R)(2S)-21j]: Brown solid
2
0
20
solid (56.2 mg, yield 93 %, dr 88:12). M.p. 172–173 °C. [α]
=
(55.1 mg, yield 95 %, dr 98:2). M.p. 145–146 °C. [α] = –2775.0 (c =
D
D
1
0.048, CHCl3). 1H NMR (500 MHz, [D ]methanol): δ = 8.16 (d, J =
–
3139.6 (c = 0.048, CHCl ). H NMR (500 MHz, [D ]methanol): δ =
3
4
4
8
.18 (d, J = 9.1 Hz, 1 H), 7.65–7.49 (m, 4 H), 7.40–7.36 (m, 2 H), 7.30
9.1 Hz, 1 H), 7.72 (d, J = 5.1 Hz, 1 H), 7.68–7.48 (m, 4 H), 7.35–7.25
(m, 2 H), 7.19–7.11 (m, 2 H), 6.70 (d, J = 2.6 Hz, 1 H), 4.72 (t, J =
4.1 Hz, 1 H), 3.39 (ddd, J = 13.2, 11.5, 5.4 Hz, 1 H), 2.97–2.91 (m, 1
H), 2.86–2.68 (m, 2 H), 2.50–2.40 (m, 1 H), 2.33–2.23 (m, 1 H), 2.22–
2.12 (m, 1 H), 2.08–2.00 (m, 1 H), 1.92 (t, J = 7.3 Hz, 3 H), 1.83–1.71
(dd, J = 9.1, 2.6 Hz, 1 H), 7.23–7.16 (m, 3 H), 6.70 (d, J = 2.6 Hz, 1
H), 4.53 (t, J = 3.5 Hz, 2 H), 3.89 (s, 3 H), 3.30–3.19 (m, 1 H), 2.90–
2
2
.79 (m, 2 H), 2.65 (dd, J = 17.8, 4.2 Hz, 1 H), 2.47–2.35 (m, 1 H),
.27–2.16 (m, 1 H), 2.01–1.82 (m, 5 H), 1.69–1.50 (m, 2 H), 1.11 (s, 3
13
13
H) ppm. C NMR (125 MHz, [D ]Methanol): δ = 183.6, 177.0, 173.0,
(m, 1 H), 1.64–1.55 (m, 1 H), 1.15 (s, 3 H) ppm. C NMR (125 MHz,
4
1
1
4
61.6, 142.6, 136.2, 134.0, 133.4, 132.9, 131.6, 131.5, 130.8, 130.3, [D ]methanol): δ = 183.6, 176.3, 173.3, 145.2, 142.7, 135.8, 134.1,
4
29.1, 128.5, 128.4, 126.9, 126.5, 115.9, 75.0, 63.6, 56.1, 53.8, 50.1,
133.6, 131.7, 131.2, 130.7, 130.4, 129.2, 128.4, 128.4, 127.9, 126.9,
126.7, 126.4, 75.1, 61.9, 53.8, 50.3, 41.3, 39.4, 21.8, 17.8, 15.6 ppm.
1.3, 38.4, 21.3, 17.6, 15.5 ppm. MS (ESI+, APCI): m/z = 604.1. HRMS
+
+
(ESI): calcd. for C H ClN NiO [M + H] 604.1508; found 604.1518. M S ( E S I + , A P C I ) : m / z = 5 8 0 . 1 . H R M S ( E S I ) : c a l c d . f o r
31 32 3 4
+
+
C H ClN NiO S [M + H] 580.0966; found 580.0976.
28
28
3
3
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-(3-methoxy-
phenyl)propanoic Acid Schiff Base Complex [(R)(2S)-21g]: Brown
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-(naphthalen-1-yl)-
propanoic Acid Schiff Base Complex [(R)(2S)-21k]: Brown solid
2
0
solid (54.4 mg, yield 90 %, dr 90:10). M.p. 165–167 °C. [α]
=
D
1
20
–
8
1
1
2850.0 (c = 0.048, CHCl ). H NMR (500 MHz, [D ]methanol): δ =
(56.8 mg, yield 91 %, dr 92:8). M.p. 145–147 °C. [α] = –2292.0 (c =
3
4
D
.17 (d, J = 9.1 Hz, 1 H), 7.70–7.47 (m, 5 H), 7.31 (dd, J = 9.1, 2.6 Hz,
H), 7.20–6.95 (m, 4 H), 6.71 (d, J = 2.6 Hz, 1 H), 4.56 (t, J = 3.4 Hz,
H), 3.85 (s, 3 H), 3.31–3.25 (m, 1 H), 2.97–2.77 (m, 2 H), 2.67 (dd,
0.05, CHCl3). 1H NMR (400 MHz, [D ]methanol): δ = 8.19 (d, J =
4
9.2 Hz, 1 H), 8.14 (d, J = 8.6 Hz, 1 H), 8.02–7.94 (m, 3 H), 7.68–7.51
(m, 7 H), 7.33 (dd, J = 9.1, 2.6 Hz, 1 H), 7.31–7.26 (m, 1 H), 6.75 (d,
J = 2.5 Hz, 1 H), 4.75 (t, J = 3.5 Hz, 1 H), 3.10–3.03 (m, 1 H), 3.03–
J = 17.8, 4.1 Hz, 1 H), 2.47–2.34 (m, 1 H), 2.30–2.21 (m, 1 H), 2.03–
1
.76 (m, 5 H), 1.68–1.47 (m, 2 H), 1.12 (s, 3 H) ppm. 13C NMR 2.93 (m, 1 H), 2.78 (dd, J = 17.9, 4.1 Hz, 1 H), 2.72–2.64 (m, 1 H),
Eur. J. Org. Chem. 2018, 1821–1832
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1828
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
2
1
.43–2.30 (m, 1 H), 2.22–2.11 (m, 1 H), 1.86 (t, J = 7.3 Hz, 3 H), 1.71–
.59 (m, 1 H), 1.39 (q, J = 9.9 Hz, 1 H), 1.22–1.05 (m, 2 H), 1.01 (s, 3
133.0, 132.6, 130.3, 130.2, 129.6, 129.2, 127.8, 126.4, 125.5, 125.0,
74.1, 60.6, 52.8, 49.6, 46.4, 40.8, 40.3, 25.1, 22.8, 22.8, 21.4, 16.8, 15.3
ppm. MS (ESI+, APCI): m/z = 554.2. HRMS (ESI): calcd. for
13
H) ppm. C NMR (150 MHz, [D ]methanol): δ = 182.1, 172.8, 171.3,
4
+
+
1
1
1
42.1, 137.0, 135.0, 133.6, 133.1, 133.0, 130.6, 130.1, 130.0, 129.5, C H ClN NiO [M + H] 554.1715; found 554.1728.
28 34 3 3
29.3, 128.5, 127.8, 127.3, 127.1, 127.0, 126.7, 125.7, 125.5, 125.3,
24.9, 63.3, 53.5, 49.0, 40.2, 38.4, 19.9, 17.1, 15.3 ppm. MS (ESI+,
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-4-methylpentanoic
Acid Schiff Base Complex [(R)(2S)-21p]: Brown solid (41.0 mg,
+
+
APCI): m/z = 624.2. HRMS (ESI): calcd. for C H ClN NiO [M + H]
6
3
4
32
3
3
24.1558; found 624.1576.
20
yield 76 %, dr 95:5). M.p. 150–152 °C. [α] = –3242.9 (c = 0.042,
D
1
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(R)-3-aminobutanoic Acid Schiff
CHCl ). H NMR (400 MHz, [D ]methanol): δ = 8.18 (d, J = 9.1 Hz, 1
3
4
H), 7.66–7.42 (m, 4 H), 7.29 (dd, J = 9.1, 2.6 Hz, 1 H), 6.90 (dt, J =
7.6, 1.0 Hz, 1 H), 6.60 (d, J = 2.6 Hz, 1 H), 4.27–4.03 (m, 2 H), 3.37–
Base Complex [(R)(2R)-21l]: Brown solid (44.5 mg, yield 87 %, dr
0:10). M.p. 240–242 °C. [α] 2D 0 = –4309.5 (c = 0.042, CHCl ). H NMR 3.32 (m, 1 H), 3.23–3.09 (m, 1 H), 2.99 (dt, J = 10.3, 3.3 Hz, 1 H),
1
9
3
(
500 MHz, [D ]methanol): δ = 8.14 (d, J = 9.1 Hz, 1 H), 7.64–7.43 (m,
2.51–2.24 (m, 6 H), 1.93 (t, J = 7.3 Hz, 3 H), 1.88–1.76 (m, 1 H), 1.35
4
1
3
4
H), 7.27 (dd, J = 9.1, 2.6 Hz, 1 H), 6.98 (d, J = 7.6 Hz, 1 H), 6.65 (d,
J = 2.6 Hz, 1 H), 4.34–4.23 (m, 1 H), 3.62–3.52 (m, 1 H), 3.44–3.35
m, 1 H), 3.29–3.16 (m, 1 H), 2.50–2.28 (m, 5 H), 2.21 (d, J = 6.6 Hz,
(d, J = 6.7 Hz, 3 H), 1.27 (s, 3 H), 0.91 (d, J = 6.6 Hz, 3 H) ppm.
C
NMR (125 MHz, CDCl ): δ = 181.5, 173.0, 170.7, 141.5, 135.8, 133.0,
3
(
132.6, 130.2, 129.6, 129.3, 127.8, 126.3, 125.6, 125.0, 74.0, 69.3, 53.1,
49.5, 40.6, 38.4, 34.0, 21.6, 21.3, 19.9, 17.0, 15.3 ppm. MS (ESI+, APCI):
3
1
H), 2.11 (dd, J = 17.5, 2.5 Hz, 1 H), 1.94 (t, J = 7.3 Hz, 3 H), 1.87–
1
3
m/z = 540.1. HRMS (ESI): calcd. for C27H32ClN NiO3 [M + H]+
+
.78 (m, 1 H), 1.27 (s, 3 H) ppm. C NMR (125 MHz, [D ]methanol):
4
3
δ = 183.1, 176.7, 172.1, 141.9, 136.7, 133.8, 133.1, 131.5, 131.3, 130.8,
540.1558; found 540.1556.
1
2
30.3, 127.9, 127.9, 126.9, 126.5, 75.9, 58.9, 53.2, 50.7, 41.7, 41.0,
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-cyclopropylpropan-
oic Acid Schiff Base Complex [(R)(2S)-21q]: Brown solid (50.0 mg,
2.4, 22.2, 17.1, 15.5 ppm. MS (ESI+, APCI): m/z = 512.1. HRMS (ESI):
+
+
calcd. for C H ClN NiO [M + H] 512.1245; found 512.1259.
25
28
3
3
2
0
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(R)-3-aminopentanoic Acid Schiff
yield 93 %, dr 98:2). M.p. 150–151 °C. [α] = –3892.1 (c = 0.038,
D
CHCl3). 1H NMR (600 MHz, [D ]methanol): δ = 8.18 (dd, J = 9.3,
4
Base Complex [(R)(2R)-21m]: Brown solid (49.4 mg, yield 94 %, dr
2.9 Hz, 1 H), 7.61–7.24 (m, 5 H), 6.92 (d, J = 7.7 Hz, 1 H), 6.58 (d, J =
6:4). M.p. 248–250 °C. [α] 2D 0 = –4370.5 (c = 0.044, CHCl ). H NMR 2.6 Hz, 1 H), 4.42–4.29 (m, 1 H), 4.18–4.02 (m, 1 H), 3.42–3.33 (m, 1
1
9
3
(
9
600 MHz, [D ]methanol): δ = 8.18 (d, J = 9.1 Hz, 1 H), 7.59 (tdd, J =
.0, 5.2, 1.6 Hz, 2 H), 7.55–7.50 (m, 1 H), 7.46 (dt, J = 7.0, 1.9 Hz, 1
H), 3.18–3.06 (m, 1 H), 2.97–2.85 (m, 1 H), 2.56–2.25 (m, 6 H), 2.02–
1.82 (m, 4 H), 1.26 (s, 3 H), 1.20–1.12 (m, 1 H), 0.85–0.73 (m, 1 H),
0.24–0.14 (m, 1 H), 0.08–0.03 (m, 1 H) ppm. 13C NMR (150 MHz,
4
H), 7.28 (dd, J = 9.1, 2.6 Hz, 1 H), 6.92 (dd, J = 7.6, 1.5 Hz, 1 H), 6.62
(
(
d, J = 2.5 Hz, 1 H), 4.22–4.10 (m, 1 H), 3.61–3.52 (m, 1 H), 3.37–3.32
m, 2 H), 3.26–3.12 (m, 1 H), 2.52–2.14 (m, 7 H), 1.93 (t, J = 7.3 Hz,
[D ]methanol): δ = 183.2, 177.1, 171.8, 142.1, 136.5, 133.9, 133.2,
4
131.7, 131.4, 130.6, 130.3, 128.8, 128.1, 126.9, 126.4, 75.9, 69.0, 53.4,
50.6, 41.9, 40.3, 22.2, 18.2, 16.9, 15.5, 6.2, 5.4 ppm. MS (ESI+, APCI):
3
H), 1.87–1.77 (m, 1 H), 1.27 (s, 3 H), 1.19 (t, J = 7.4 Hz, 3 H) ppm.
1
3
m/z = 538.1. HRMS (ESI): calcd. for C27H30ClN NiO3+ [M + H]+
C NMR (150 MHz, [D ]methanol): δ = 183.2, 176.8, 173.1, 142.2,
4
3
1
1
36.9, 134.0, 133.2, 131.7, 131.3, 130.6, 130.3, 128.8, 128.1, 126.8, 538.1402; found 538.1413.
26.3, 75.8, 64.9, 53.3, 50.6, 41.6, 40.2, 30.6, 22.2, 17.2, 15.5, 11.9
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(S)-3-amino-3-cyclohexylpropanoic
Acid Schiff Base Complex [(R)(2S)-21r]: Brown solid (49.3 mg,
ppm. MS (ESI+, APCI): m/z = 526.1. HRMS (ESI): calcd. for
C H ClN NiO [M + H] 526.1402; found 526.1408.
+
+
26
30
3
3
2
0
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(R)-3-aminoheptanoic Acid Schiff
yield 85 %, dr 94:6). M.p. 155–157 °C. [α] = –2770.0 (c = 0.04,
D
1
CHCl ). H NMR (400 MHz, [D ]methanol): δ = 8.17 (d, J = 9.1 Hz, 1
3
4
Base Complex [(R)(2R)-21n]: Brown solid (53.7 mg, yield 97 %, dr
H), 7.63–7.42 (m, 4 H), 7.28 (dd, J = 9.1, 2.6 Hz, 1 H), 6.95–6.86 (m,
4:6). M.p. 110–112 °C. [α] 2D 0 = –3400.0 (c = 0.046, CHCl ). H NMR 1 H), 6.58 (d, J = 2.6 Hz, 1 H), 4.27–4.13 (m, 1 H), 4.04–3.88 (m, 1 H),
1
9
3
(
400 MHz, [D ]methanol): δ = 8.17 (d, J = 9.1 Hz, 1 H), 7.65–7.42 (m,
3.39–3.33 (m, 1 H), 3.24–3.13 (m, 1 H), 3.09–3.00 (m, 1 H), 2.64–2.25
(m, 7 H), 1.99 (d, J = 13.1 Hz, 1 H), 1.91 (t, J = 7.3 Hz, 3 H), 1.86–
1.70 (m, 5 H), 1.52–1.38 (m, 1 H), 1.27 (s, 3 H), 1.17–1.09 (m, 1 H),
4
4
2
3
H), 7.29 (dd, J = 9.1, 2.6 Hz, 1 H), 6.96–6.86 (m, 1 H), 6.61 (d, J =
.5 Hz, 1 H), 4.18 (td, J = 12.3, 6.7 Hz, 1 H), 3.60–3.33 (m, 3 H), 3.26–
.10 (m, 1 H), 2.51–2.11 (m, 7 H), 1.93 (t, J = 7.3 Hz, 3 H), 1.88–1.74
0.81–0.59 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl ): δ = 181.4, 173.3,
3
(
m, 2 H), 1.60–1.36 (m, 2 H), 1.27 (s, 3 H), 1.24–1.12 (m, 1 H), 0.98 (t,
170.7, 141.5, 135.7, 133.0, 132.6, 130.3, 130.2, 129.6, 129.2, 128.0,
126.3, 125.6, 124.9, 74.2, 68.1, 52.8, 49.6, 43.1, 40.6, 37.7, 31.3, 29.8,
13
J = 7.4 Hz, 3 H) ppm. C NMR (125 MHz, [D ]methanol): δ = 181.5,
4
1
1
2
72.7, 170.7, 141.4, 135.6, 132.9, 132.6, 130.2, 129.7, 129.2, 127.6, 26.4, 26.3, 26.0, 21.5, 16.7, 15.3 ppm. MS (ESI+, APCI): m/z = 580.2.
+
+
26.3, 125.5, 125.0, 74.1, 62.7, 52.9, 49.5, 40.8, 40.4, 36.8, 29.1, 22.9, HRMS (ESI): calcd. for C H ClN NiO [M + H] 580.1871; found
30
36
3
3
1.5, 16.8, 15.3, 14.1 ppm. MS (ESI+, APCI): m/z = 554.2. HRMS (ESI):
580.1876.
+
+
calcd. for C H ClN NiO [M + H] 554.1715; found 554.1720.
28
34
3
3
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(R)-3-amino-4-(2,4,5-trifluoro-
phenyl)butanoic Acid Schiff Base Complex [(R)(2R)-21s]: Brown
Nickel(II) (R)-N-(2-Benzoyl-4-chlorophenyl)-1-ethyl-2-methyl-
pyrrolidine-2-carboxamide/(R)-3-amino-5-methylhexanoic Acid
Schiff Base Complex [(R)(2R)-21o]: Brown solid (50.4 mg, yield
2
0
solid (55.86 mg, yield 87 %, dr 95:5). M.p. 140–141 °C. [α]
=
D
1 %, dr 92:8). M.p. 248–251 °C. [α]D = –3029.5 (c = 0.044, CHCl3). –2814.0 (c = 0.05, CHCl3). 1H NMR (500 MHz, [D ]methanol): δ =
2
0
9
4
1
H NMR (400 MHz, [D ]methanol): δ = 8.16 (d, J = 9.1 Hz, 1 H), 7.66–
8.15 (d, J = 9.1 Hz, 1 H), 7.62–7.48 (m, 2 H), 7.46–7.34 (m, 2 H), 7.28
(dd, J = 9.1, 2.5 Hz, 1 H), 7.12 (td, J = 9.9, 6.6 Hz, 1 H), 7.03 (ddd,
J = 10.7, 8.7, 6.7 Hz, 1 H), 6.59 (d, J = 2.6 Hz, 1 H), 6.49–6.38 (m, 1
4
7
1
3
.46 (m, 4 H), 7.28 (dd, J = 9.1, 2.6 Hz, 1 H), 6.96 (dt, J = 8.3, 1.4 Hz,
H), 6.62 (d, J = 2.6 Hz, 1 H), 4.32–4.18 (m, 1 H), 3.58–3.49 (m, 1 H),
.41–3.33 (m, 2 H), 3.26–3.10 (m, 1 H), 2.56–2.27 (m, 6 H), 2.17 (dd, H), 4.38 (dd, J = 13.8, 6.9 Hz, 1 H), 4.20 (ddd, J = 13.4, 11.4, 5.7 Hz,
J = 17.5, 2.5 Hz, 1 H), 1.92 (t, J = 7.3 Hz, 3 H), 1.86–1.68 (m, 2 H),
1 H), 4.01–3.91 (m, 1 H), 3.62 (tdd, J = 6.9, 4.3, 2.5 Hz, 1 H), 3.51–
1
.27 (s, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 0.73 (d, J = 6.5 Hz, 3 H) ppm.
3.33 (m, 2 H), 2.58–2.28 (m, 5 H), 2.09 (dd, J = 17.6, 2.6 Hz, 1 H),
1
3
13
C NMR (125 MHz, CDCl ): δ = 181.5, 172.7, 170.5, 141.4, 135.5,
2.01 (t, J = 7.3 Hz, 3 H), 1.89–1.78 (m, 1 H), 1.31 (s, 3 H) ppm.
C
3
Eur. J. Org. Chem. 2018, 1821–1832
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1829 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
NMR (125 MHz, [D ]methanol): δ = 183.4, 176.4, 173.6, 157.6 (ddd,
J = 245.1, 9.5, 2.2 Hz), 150.6 (dt, J = 250.2, 13.8 Hz), 148.07 (ddd,
J = 244.1, 12.5, 3.1 Hz), 142.2, 136.5, 134.0, 133.4, 131.3, 131.0, 130.4,
(3 × 50 mL). The combined organic extracts were washed with brine
(100 mL), dried (Na SO ), filtered, and evaporated to dryness under
4
2
4
vacuum to afford the crude product, which was loaded on a silica
gel column and immediately chromatographed (petroleum ether/
EtOAc 3:1) to furnish the pure product as a white solid (yield 0.34 g,
1
30.2, 128.0, 127.8, 126.8, 126.6, 122.1 (dt, J = 18.6, 5.0 Hz), 120.0
(dd, J = 19.3, 5.9 Hz), 106.9 (dd, J = 28.9, 21.2 Hz), 75.7, 64.0, 53.2,
+
5
0.9, 41.4, 39.2, 35.9, 22.6, 18.0, 15.6 ppm. MS (ESI+, APCI): m/z =
92 %). MS (ESI+, APCI): m/z = 250.1 [M + H] .
+
+
6
42.1. HRMS (ESI): calcd. for C H ClF N NiO [M + H] 642.1276;
31 29 3 3 3
tert-Butyl (1S)-3-[3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-
exo-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylcarbamate [(S)-
26]: Amine 25 (0.28 g, 1.2 mmol) was slurried in 1,2-dichloroethane
(10 mL) and treated with a solution of (S)-24 (0.25 g, 1 mmol) as a
found 642.1287.
(
S)-3-Amino-3-phenylpropanoic Acid [(S)-4a]: A solution of
(R)(2S)-21a (3.0 g, 5.22 mmol) in MeOH (40 mL) was added to a
stirring solution of 3
N
HCl in MeOH (1:1 v/v, 80 mL) at 50 °C. The 1,2-dichloroethane concentrate, and then acetic acid (12 μL,
mixture was gently heated under reflux for 30 min and then evapo- 0.2 mmol) was added. To the resultant solution was added sodium
rated to dryness. Water (50 mL) was added, and the resultant mix- triacetoxyborohydride (0.32 g, 1.5 mmol) portionwise with the tem-
ture was treated with an excess of concentrated NH OH and ex-
perature maintained below 30 °C. The resultant slurry was stirred at
4
tracted with CH Cl . The CH Cl extracts were dried (Na SO ), and
ambient temperature for 24 h and then diluted with H O (30 mL)
2
2
2
2
2
4
2
the solvents were evaporated under vacuum to afford the free chiral
ligand (R)-17 (1.85 g, yield 95 %). The aqueous phase was evapo-
and dichloromethane (30 mL). The aqueous layer was adjusted to
pH 11–12 by the addition of a 2 M sodium hydroxide solution. The
rated under vacuum and dissolved in a minimum amount of H O,
layers were separated, and the aqueous phase was extracted with
dichloromethane (2 × 30 mL). The organic extracts were combined,
washed with brine (100 mL), dried (Na SO ), filtered, and evapo-
2
and the solution was loaded on a Dowex 50X2-100 ion-exchange
column, which was washed with H O until neutral. The column was
2
2
4
then washed with 10 % aqueous NH OH. The first fraction (500 mL)
rated to dryness under vacuum to afford the crude product, which
was loaded on a silica gel column and immediately chromato-
graphed (dichloromethane/ methanol 15:1) to furnish the pure
4
was collected, and the solvents were evaporated under vacuum to
afford the corresponding amino acid (S)-4a as a white solid
2
0
(
[
(
(
800 mg, yield 92 %). M.p. 223–224 °C. [α] = –12 (c = 0.1, H O). product as a white solid (yield: 0.33 g, 71 %). MS (ESI+, APCI): m/z =
D
2
20
1
+
α] = –7.7 (c = 0.1, H O). H NMR (500 MHz, D O): δ = 7.58–7.41
m, 5 H), 4.70 (t, J = 7.3 Hz, 1 H), 3.11–2.86 (m, 2 H) ppm. C NMR
125 MHz, D O): δ = 175.93, 135.66, 129.38, 129.27, 126.91, 52.29,
468.3 [M + H] .
D
2
2
13
4,4-Difluoro-N-{(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-tri-
2
azol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}-
cyclohexanecarboxamide [(S)-29]: A solution of (S)-26 (93.4 mg,
3
9.48 ppm. MS (ESI+, APCI): m/z = 166.1. HRMS (ESI): calcd. for
+
+
C H NO [M + H] 166.0863; found 166.0858.
9
11
2
0.2 mmol) in methanol (5 mL) was cooled to 0 °C. A 4 N HCl/dioxane
(
2
S)-3-tert-Butoxycarbonylamino-3-phenylpropionic Acid [(S)-
2]: To a solution of (S)-4a (0.33 g, 2 mmol) in NaHCO (50 % sat.
solution (5 mL) was added slowly to the reaction mixture, which
was then stirred at room temperature for 3 h. The resultant solution
was concentrated under reduced pressure to afford the crude inter-
mediate product (S)-27. Amine (S)-27 was slurried in dichloro-
methane (5 mL) and treated with triethylamine (138.7 μL, 1 mmol),
followed by 4,4-difluorocyclohexanecarboxylic acid (28, 39.4 mg,
3
aq., 3 mL) were added di-tert-butyl dicarbonate (0.52 g, 2.2 mmol)
and acetonitrile (10 mL). The reaction mixture was stirred at room
temperature for 24 h. The solution was concentrated under reduced
pressure and diluted with H O (30 mL), and the aqueous layer was
2
acidified with 1
combined organic extracts were washed with brine (100 mL), dried
Na SO ), and filtered, and the solvents were evaporated to dryness
N HCl and extracted with EtOAc (3 × 50 mL). The
0
.24 mmol), EDCI (46.0 mg, 0.24 mmol), and HOBT (32.4 mg,
0.24 mmol). The reaction mixture was stirred at room temperature
(
2
4
for a further 12 h, and diluted with H O (30 mL) and dichloro-
2
under vacuum to afford the crude product, which was loaded on a
silica gel column, and immediate chromatography (petroleum
ether/EtOAc 1:2) furnished the pure product as a white solid (yield:
methane (30 mL). The aqueous layer was adjusted to pH 11–12 by
the addition of a 2
M sodium hydroxide solution. The layers were
separated, and the aqueous phase was extracted with dichloro-
methane (2 × 30 mL). The organic extracts were combined, washed
with brine (100 mL), dried (Na SO ), filtered, and evaporated to dry-
0
5
.52 g, 98 %). 1H NMR (400 MHz, CDCl ): δ = 7.34–7.24 (m, 5 H),
3
.48 (br s, 1 H), 5.11–4.93 (m, 1 H), 2.84 (s, 2 H), 1.41 (br s, 9 H) ppm.
2
4
–
MS (ESI+, APCI): m/z = 264.0 [M – H] .
ness under vacuum to the afford crude product, which was loaded
on a silica gel column and immediately chromatographed (dichloro-
methane/methanol 10:1) to furnish the pure product as a white
tert-Butyl (S)-3-Hydroxy-1-phenylpropylcarbamate [(S)-23]: A
mixture of (S)-22 (0.40 g, 1.5 mmol) was slurried in THF (5 mL)
2
5
under an atmosphere of nitrogen and cooled to 0 °C. BH ·THF (1
M
solid (yield: 76.9 mg, 75 %, >98.2 % ee). [α]
D
= –28.4 (c = 0.5, CHCl
H NMR (400 MHz, CDCl ): δ = 7.35–7.31 (m, 2 H), 7.28–7.26 (m, 3
3
3
).
3
1
solution in THF, 3 mL) was added slowly to the reaction mixture,
which was then stirred for a further 5 h. The excess BH ·THF was
quenched by the addition of acetone. The THF was removed by
concentration under reduced pressure, and the residue was dis-
H), 6.82–6.66 (br m, 1 H), 5.12–5.07 (m, 1 H), 4.32–4.26 (m, 1 H), 3.40
(br d, 2 H), 3.01–2.94 (m, 1 H), 2.48 (s, 3 H), 2.44 (t, J = 8 Hz, 2 H),
2.28–1.64 (m, 19 H), 1.37 (d, J = 4 Hz, 6 H) ppm. 13C NMR (151 MHz,
3
solved in H O (40 mL) and extracted with dichloromethane
CDCl
58.99, 58.37, 51.94, 47.99, 47.30, 42.74, 35.40, 35.28, 34.66, 32.95
= 6 Hz), 32.82, 32.79, 32.63 (J13C,19
= 4.5 Hz), 26.66, 26.62,
25.98 (J13C,19 = 9 Hz), 25.89 (J13C,19
= 9 Hz), 25.80, 21.63, 13.07 ppm.
MS (ESI+, APCI): m/z = 514.3 [M + H] . HRMS (ESI): calcd. for C29
3
): δ = 173.71, 159.23, 150.70, 141.97, 128.77, 127.49, 126.49,
2
(
(
3 × 50 mL). The combined organic extracts were washed with brine
100 mL), dried (Na SO ), filtered, and evaporated to dryness under
(J13C,19
2
4
F
F
vacuum to afford the crude product (0.39 g, 104 %). MS (ESI+, APCI):
F
F
+
+
m/z = 252.1 [M + H] .
H
42
+
+
F N O [M + H] 514.3552; found 514.3551.
2
5
tert-Butyl (S)-3-Oxo-1-phenylpropylcarbamate [(S)-24]: A solu-
tion of (S)-23 (0.39 g, 1.5 mmol) in dichloromethane (10 mL) was
cooled to 0 °C. Dess–Martin periodinane (0.76 g, 1.8 mmol) was
added slowly to the reaction mixture, which was then stirred at
Acknowledgments
room temperature for 1 h. NaHCO3 (sat. aq., 30 mL) was added, We gratefully acknowledge financial support from the National
and the reaction mixture was extracted with dichloromethane Natural Science Foundation of China (81620108027
Eur. J. Org. Chem. 2018, 1821–1832
www.eurjoc.org
1830
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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Keywords: Amino acids · Chemical resolution · Nickel ·
Nonracemizable ligands · Antiviral agents
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